Tau accumulation patterns in PSP constrain mechanisms and quantify cell-to-cell and cell-autonomous aggregation rates

Protein aggregates are a hallmark of neurodegenerative disease, yet the molecular processes that control their appearance are still poorly understood. In particular, it is unknown to what degree the development of aggregates in one cell is triggered by nearby aggregated cells, as opposed to cell-autonomous processes. Here we develop a cell-level computational model to test alternative hypotheses of disease progression from human data and demonstrate its applicability in the primary tauopathy Progressive Supranuclear Palsy. From brain slices stained for aggregated tau, we quantify the contribution of cell-to-cell and cell-autonomous processes to the proliferation of aggregates across different brain regions and disease stages. We find that the triggering of aggregation by nearby aggregated cells, over distances in the order of 100µm, is the major driver of disease progression. Our computational model can then simulate interventions to evaluate potential therapeutic strategies in a virtual reconstruction of a human primary neurodegenerative tauopathy.